Loic Le Mignot

Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype

BACKGROUND Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. OBJECTIVE We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. METHODS We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. RESULTS Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. CONCLUSION Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.

Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France.

Background: Chronic granulomatous disease (CGD) is a rare inherited phagocytic disorder resulting in an increased susceptibility to infections including invasive fungal diseases (IFDs) and inflammatory complications. This study is aimed at assessing the incidence, prevalence, and outcome of IFDs among CGD patients followed in France. Methods: CGD patients were identified through the French national registry for primary immunodeficiencies (PID) held by the French national reference Centre of PID (Centre de Référence Déficits Immunitaires Héréditaires), which comprises a total of 3083 patients including 155 with CGD followed between 1976 and 2008. A questionnaire was filled out for each episode of IFD. Information retrieved included a description of the IFD using the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group IFD definition criteria. Results: Of CGD patients, 42.6% (66/155) developed at least 1 episode of IFD. Overall incidence of IFD was 0.040/patient-years (1862 patient-years of total follow-up). IFD incidence was found to be significant while receiving itraconazole prophylaxis compared with no prophylaxis (0.027 vs. 0.053 IFD/patient-years; P < 0.01). Median age at IFD diagnosis was 6.5 years (3.3–11.3). The most common fungal genus was Aspergillus sp. accounting for 40% of all IFDs. Of the IFDs, 42.5% were proven, 30.0% probable, and 27.5% possible. Of all IFD episodes, 52.5% were treated by antifungal monotherapy, mostly by amphotericin B. Survival was reduced in IFD patients compared with those without it (log-rank = 0.04). Conclusions: IFDs are a frequent and life-threatening complication in CGD patients. Itraconazole significantly reduces its incidence and should be recommended in absence of better alternatives.